The early metabolic stability assessment of novel potential drug candidates remains today a major challenge in drug development. Although significant advancements have been made for CYP-mediated metabolism, action mechanism of other non-CYP enzymes remains poorly understood. In particular, Aldehyde Oxidase (AOX) has emerged as a key enzyme responsible for several clinical candidate failures (e.g., carbazeran, GDC-0834). Indeed, AOX has a broad substrate specificity, catalyzing aza-aromatic oxidation and amide hydrolysis, common moieties in drugs. In the present study, we designed a large dataset of potential AOX substrates, covering a diverse chemical domain of commonly used drugs and drug candidates to obtain a sound base for further mechanistic investigation and modeling studies. Thus, more than 300 compounds were synthesized or acquired and tested in human liver cytosol (HLC) for assessing AOX-mediated metabolism. Thus, combining <i>in vitro</i> experimental results and DFT calculations, important structure-metabolic stability relationships were identified. As a result, we defined useful guidelines for tuning AOX susceptibility of lead compounds, and developed a new <i>in silico</i> model for human AOX-mediated metabolism prediction.

Chemical insights into human aldehyde oxidase-mediated metabolism

256th National Meeting (2018)

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